Pemafibrate dosing regimens

ABSTRACT

To provide a medicament for safely treating a patient in need of treatment with pemafibrate, a salt thereof, or a solvate of any of these (hereinafter also referred to as pemafibrate therapy).A medicament for treating a patient in need of pemafibrate therapy, the medicament comprising the step of avoiding or suspending concomitant use of pemafibrate, a salt thereof, or a solvate of any of these as an active ingredient in order to suppress an increase in plasma concentration of pemafibrate when the treatment is combined with a medicament containing an OATP1B inhibitor, or the step of reducing the dose of pemafibrate, a salt thereof, or a solvate of any of these.

TECHNICAL FIELD

The present invention relates to a new medicament for efficient and safeuse of pemafibrate, a salt thereof, or a solvate of any of these.

BACKGROUND ART

Pemafibrate (Chemical name:(2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoicacid), a salt thereof, or a solvate of any of these are compounds havingPPARα activity and are known to be useful for the prevention and/ortreatment of diseases such as dyslipidemia (Patent Literature 1).

Rifampicin (2S, 12Z, 14E, 16S, 17S, 18R, 19R, 20R, 21S, 22R, 23S,24E)5,6,9,17,19-pentahydroxy-23-methoxy-2,4,12,20,22-heptamethyl-8-(4-methylpiperazin-1-yliminomethyl)1,11-dioxo-1,2-dihydro-7-(epoxypentadeca[1,11,13]trienimino)[2,1-b]furan-21ylacetate is an organic compound represented by the following formula (1)

which is an antibiotic listed in the WHO-Essential Drug Model List (WHOModel List of Essential Medicines, 19th List).

Clarithromycin is a compound represented by the following formula (2)

which is an antibiotic listed in the WHO-Essential Drug Model List (WHOModel List of Essential Medicines, 19th List).

Cyclosporine is an immunosuppressive agent used to suppress rejection inthe organ transplantation of kidneys, liver, heart or bone-marrow and totreat graft-versus-host diseases, which is listed in the WHO-EssentialDrug Model List (WHO Model List of Essential Medicines, 19th List).

Clopidogrel (Chemical Name: methyl(2S)-2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate),a salt thereof, or a solvate of any of these are compounds known to haveplatelet aggregation inhibitory and antithrombotic activities (PatentLiterature 2).

Multiple drugs are often prescribed for therapeutic purposes in theclinical practice, and attention should be paid to interactions betweenthe drugs used concomitantly. Because drug interactions may causeserious side effects and/or diminish therapeutic effects, the propertyand extent of potential drug interactions should be adequately assessedand addressed in the development of new drugs so that they do not pose adisadvantage to the patients.

PRIOR ART DOCUMENTS Patent Literature

-   [Patent Literature 1] WO 2005/023777 pamphlet-   [Patent Literature 2] JP-B-Hei 6-45622

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The pharmacokinetics of pemafibrate, a salt thereof, or a solvate of anyof these and their interactions with other drugs are not described inthe above Prior art Documents.

The present invention addresses to provide a medicament for safetreatment of a patient in need of treatment with pemafibrate, a saltthereof, or a solvate of any of these (hereinafter also referred to aspemafibrate therapy).

Means for Solving the Problem

In order to solve the above problems, the present inventors conductedextensive researches, and as a result, the present inventors have foundthat caution should be exercised when pemafibrate is used concomitantlywith rifampicin because of the rise in the plasma concentration ofpemafibrate. We also found that the interaction caused by theconcomitant use of pemafibrate with rifampicin was due to the fact thatrifampicin is an inhibitor of organic anion-transporting polypeptides(OATP1B), which is a hepatic uptake transporter. The present inventorshave found that a patient in need of treatment with pemafibrate, a saltthereof, or a solvate of any of these can be safely treated by avoidingor suspending the concomitant use of pemafibrate with an OATP1Binhibitor such as rifampicin, or by reducing the dose of pemafibrate, asalt thereof, or a solvate of any of these, and the present inventionhas been completed.

In addition, it was found that concomitant use of pemafibrate withclarithromycin, cyclosporine, or clopidogrel also increased the plasmaconcentration of pemafibrate, requiring caution when concomitantly used.

The present invention also found that the combined interaction ofpemafibrate with clarithromycin, cyclosporine, or clopidogrel was due toclarithromycin, cyclosporine, or clopidogrel being a drug that inhibitsOATP1B and further inhibits the action of certain cytochrome P450(CYPs). The present inventors have found that a patient in need oftreatment with pemafibrate a salt thereof, or a solvate of any of thesecan be safely treated by avoiding or suspending the concomitant use ofpemafibrate with an OATP1B inhibitor and/or a CYP inhibitor, or byreducing the dose of pemafibrate, a salt thereof, or a solvate of any ofthese, and the present invention has been completed.

The present invention provides the following [1] to [58].

[1] A medicament comprising pemafibrate, a salt thereof, or a solvate ofany of these as an active ingredient, for use in the treatment of apatient in need of pemafibrate therapy, in order to suppress an increasein plasma concentration of pemafibrate when the treatment is concomitantuse of pemafibrate with a medicament comprising an OATP1B inhibitor, themedicament comprising a step of avoiding or suspending the concomitantuse or a step of reducing the dose of pemafibrate, a salt thereof, or asolvate of any of these.[2] The medicament according to [1], wherein the pemafibrate, a saltthereof, or a solvate of any of these is pemafibrate.[3] The medicament according to [1] or [2], wherein the OATP1B inhibitoris one or more drugs selected from the group consisting ofclarithromycin, rifampicin, cyclosporine, a combination agent oflopinavir and ritonavir, a combination agent of atazanavir andritonavir, a combination agent of dalnavir and ritonavir, clopidogrel,eltrombopag, a combination agent of saquinavir and ritonavir, acombination agent of tipranavir and ritonavir, and gemfibrozil.[4] The medicament according to any one of [1] to [3], wherein thepatient in need of pemafibrate therapy is a patient with one or morediseases selected from the group consisting of hyperlipidemia,dyslipidemia, arteriosclerosis, diabetes mellitus, diabeticcomplications, inflammation, non-alcoholic steatohepatitis, primarybiliary cirrhosis, and heart disease.[5] The medicament according to any one of [1] to [4], wherein thepatient is a patient further in need of pemafibrate therapy duringtreatment with an OATP1B inhibitor.[6] The medicament according to any one of [1] to [4], wherein thepatient is a patient further in need of treatment with an OATP1Binhibitor during pemafibrate therapy.[7] The medicament according to any one of [1] to [6], wherein the stepof reducing the dose of pemafibrate, a salt thereof, or a solvate of anyof these is to reduce the dose of pemafibrate, a salt thereof, or asolvate of any of these, compared with the dose when the drug isadministered alone, to ½ or less.[8] The medicament according to any one of [1] to [7], wherein the stepof reducing the dose of pemafibrate, a salt thereof, or a solvate of anyof these is to set the dose of pemafibrate, a salt thereof, or a solvateof any of these as 0.1 to 0.2 mg/day.[9] The medicament according to any one of [1] to [8], wherein thepemafibrate, a salt thereof, or a solvate of any of these isadministered twice per day.[10] A pharmaceutical kit comprising (A) a medicament comprisingpemafibrate, a salt thereof, or a solvate of any of these as an activeingredient; and (B) an instruction to avoid or suspend concomitant useof the (A) with a medicament comprising an OATP1B inhibitor, or toreduce the dose of pemafibrate, a salt thereof, or a solvate of any ofthese at the time of the concomitant use.[11] The pharmaceutical kit according to [10], wherein the pemafibrate,a salt thereof, or a solvate of any of these is pemafibrate.[12] The pharmaceutical kit according to [10] or [11], wherein theOATP1B inhibitor is one or more drugs selected from the group consistingof clarithromycin, rifampicin, cyclosporine, a combination agent oflopinavir and ritonavir, a combination agent of atazanavir andritonavir, a combination agent of dalnavir and ritonavir, clopidogrel,eltrombopag, a combination agent of saquinavir and ritonavir, acombination agent of tipranavir and ritonavir, and gemfibrozil.[13] The pharmaceutical kit according to anyone of [10] to [12], whereinthe medicament of (A) is a drug for the prevention and/or treatment forone or more diseases selected from the group consisting ofhyperlipidemia, dyslipidemia, arteriosclerosis, diabetes mellitus,diabetic complications, inflammation, non-alcoholic steatohepatitis,primary biliary cirrhosis, and heart disease.[14] The pharmaceutical kit according to any one of [10] to [13],instructing to reduce the dose of pemafibrate, a salt thereof, or asolvate of any of these, compared with the dose when the drug isadministered alone, to ½ or less.[15] The pharmaceutical kit according to any one of [10] to [14],instructing to set the dose of pemafibrate, a salt thereof, or a solvateof any of these as 0.1 to 0.2 mg per day.[16] The pharmaceutical kit according to any one of [10] to [15],instructing to administer pemafibrate, a salt thereof, or a solvate ofany of these twice per day.[17] The pharmaceutical kit according to any one of [10] to [16],wherein the instruction is a package insert, a package label, or a usermanual.[18] A medicament comprising pemafibrate, a salt thereof, or a solvateof any of these as an active ingredient, for use in the treatment of apatient in need of pemafibrate therapy, in order to suppress an increasein plasma concentration of pemafibrate when the treatment is concomitantuse of pemafibrate with a medicament comprising a CYP inhibitor, themedicament comprising a step of avoiding or suspending the concomitantuse or a step of reducing the dose of pemafibrate, a salt thereof, or asolvate of any of these.[19] The medicament according to [18], wherein the pemafibrate, a saltthereof, or a solvate of any of these is pemafibrate.[20] The medicament according to [18] or [19], wherein the CYP inhibitoris a drug that inhibits CYP3A.[21] The medicament according to [20], wherein the drug that inhibitsCYP3A is one or more drugs selected from the group consisting ofclarithromycin, cyclosporine, cobicistat, indinavir, itraconazole,ritonavir, telaprevir, voriconazole, nelfinavir, saquinavir, boceprevir,conivaptan, ketoconazole, a combination agent of lopinavir andritonavir, mibefradil, nefazodone, posaconazole, telithromycin,fluconazole, amprenavir, aprepitant, atazanavir, ciprofloxacin,crizotinib, a combination agent of darnavir and ritonavir, diltiazem,erythromycin, fosamprenavir, imatinib, istradefylline, miconazole,tofisopam, casopitant, dronedarone, and verapamil.[22] The medicament according to [18] or [19], wherein the CYP inhibitoris a drug that inhibits CYP2C8.[23] The medicament according to [22], wherein the drug that inhibitsCYP2C8 is one or more drugs selected from the group consisting ofgemfibrozil, clopidogrel, cyclosporine, deferasirox, and teriflunomide.[24] The medicament according to [18] or [19], wherein the CYP inhibitoris a drug that inhibits CYP2C9.[25] The medicament according to [24], wherein the drug that inhibitsCYP2C9 is one or more drugs selected from the group consisting of afluorouracil derivative, carmofur, sulfaphenazole, amiodarone, bucolome,cyclosporine, fluconazole, miconazole, and oxandrolone.[26] The medicament according to any one of [19] to [25], wherein thepatient in need of pemafibrate therapy is a patient with one or morediseases selected from the group consisting of hyperlipemia,dyslipidemia, arteriosclerosis, diabetes mellitus, diabeticcomplications, inflammation, non-alcoholic steatohepatitis, primarybiliary cirrhosis, and heart disease.[27] The medicament according to any one of [19] to [26], wherein thepatient is a patient further in need of pemafibrate therapy duringtreatment with a CYP inhibitor.[28] The medicament according to any of [19] to [26], wherein thepatient is a patient further in need of treatment with a CYP inhibitorduring pemafibrate therapy.[29] The medicament according to any one of [19] to [28], wherein thestep of reducing the dose of pemafibrate, a salt thereof, or a solvateof any of these is to reduce the dose of pemafibrate, a salt thereof, ora solvate of any of these, compared with the dose when the drug isadministered alone, to ½ or less.[30] The medicament according to any one of [19] to [29], wherein thestep of reducing the dose of pemafibrate, a salt thereof, or a solvateof any of these is to set the dose of pemafibrate, a salt thereof, or asolvate of any of these as 0.1 to 0.2 mg/day.[31] The medicament according to any one of [19] to [30], wherein thepemafibrate, a salt thereof, or a solvate of any of these isadministered twice per day.[32] The medicament according to any one of [19] to [31], wherein theCYP inhibitor is a drug that further inhibits OATP1B.[33] A pharmaceutical kit comprising (A) a medicament comprisingpemafibrate, a salt thereof, or a solvate of any of these as an activeingredient; and (B) an instruction to avoid or suspend concomitant useof the (A) with a medicament comprising a CYP inhibitor, or to reducethe dose of pemafibrate, a salt thereof, or a solvate of any of these atthe time of the concomitant use.[34] The pharmaceutical kit according to [33], wherein the pemafibrate,a salt thereof, or a solvate of any of these is pemafibrate.[35] The pharmaceutical kit according to [33] or [34], wherein the CYPinhibitor is a drug that inhibits CYP3A.[36] The pharmaceutical kit according to [35], wherein the drug thatinhibits CYP3A is one or more drugs selected from the group consistingof clarithromycin, cyclosporine, cobicistat, indinavir, itraconazole,ritonavir, telaprevir, voriconazole, nelfinavir, saquinavir, boceprevir,conivaptan, ketoconazole, a combination agent of lopinavir andritonavir, mibefradil, nefazodone, posaconazole, telithromycin,fluconazole, amprenavir, aprepitant, atazanavir, ciprofloxacin,crizotinib, a combination agent of darnavir and ritonavir, diltiazem,erythromycin, fosamprenavir, imatinib, istradefylline, miconazole,tofisopam, casopitant, dronedarone, and verapamil.[37] The pharmaceutical kit according to [33] or [34], wherein the CYPinhibitor is a drug that inhibits CYP2C8.[38] The pharmaceutical kit according to (37), wherein the drug thatinhibits CYP2C8 is one or more drugs selected from the group consistingof gemfibrozil, clopidogrel, cyclosporine, deferasirox, andteriflunomide.[39] The pharmaceutical kit according to [33] or [34], wherein the CYPinhibitor is a drug that inhibits CYP2C9.[40] The pharmaceutical kit according to [39], wherein the drug thatinhibits CYP2C9 is one or more drugs selected from the group consistingof a fluorouracil derivative, carmofur, sulfaphenazole, amiodarone,bucolome, cyclosporine, fluconazole, miconazole, and oxandrolone.[41] The pharmaceutical kit according to any one of [33] to [40],wherein the medicament of (A) is a drug for the prevention and/ortreatment for one or more diseases selected from the group consisting ofhyperlipidemia, dyslipidemia, arteriosclerosis, diabetes mellitus,diabetic complications, inflammation, non-alcoholic steatohepatitis,primary biliary cirrhosis, and heart disease.[42] The pharmaceutical kit according to any one of [33] to [41],instructing to reduce the dose of pemafibrate, a salt thereof, or asolvate of any of these, compared with the dose when the drug isadministered alone, to ½ or less.[43] The pharmaceutical kit according to any one of [33] to [42],instructing to set the dose of pemafibrate, a salt thereof, or a solvateof any of these as 0.1 to 0.2 mg per day.[44] The pharmaceutical kit according to any one of [33] to [43],instructing to administer pemafibrate, a salt thereof, or a solvate ofany of these twice per day.[45] The pharmaceutical kit according to any one of [33] to [44],wherein the instruction is a package insert, a package label, or a usermanual.[46] The pharmaceutical kit according to anyone of [33] to [45], whereinthe CYP inhibitor is a drug that further inhibits OATP1B.[47] A medicament comprising pemafibrate, a salt thereof, or a solvateof any of these as an active ingredient, for use in the treatment of apatient in need of pemafibrate therapy, in order to suppress an increasein plasma concentration of pemafibrate when the treatment is concomitantuse of pemafibrate with a medicament comprising an OATP1B inhibitor,comprising an optional step of avoiding or suspending the concomitantuse or reducing the dose of pemafibrate, a salt thereof, or a solvate ofany of these.[48] A pharmaceutical kit comprising (A) a medicament comprisingpemafibrate, a salt thereof, or a solvate of any of these as an activeingredient; and (B) an instruction optionally to avoid or suspendconcomitant use of the (A) with a medicament comprising an OATP1Binhibitor, or to reduce the dose of pemafibrate, a salt thereof, or asolvate of any of these at the time of the concomitant use.[49] A medicament comprising pemafibrate, a salt thereof, or a solvateof any of these as an active ingredient, for use in the treatment of apatient in need of pemafibrate therapy, in order to suppress an increasein plasma concentration of pemafibrate when the treatment is concomitantuse of pemafibrate with a medicament comprising a CYP inhibitor,comprising an optional step of avoiding or suspending the concomitantuse or reducing the dose of pemafibrate, a salt thereof, or a solvate ofany of these.[50] A pharmaceutical kit comprising (A) a medicament comprisingpemafibrate, a salt thereof, or a solvate of any of these as an activeingredient; and (B) an instruction optionally to avoid or suspendconcomitant use of the (A) with a CYP inhibitor, or to reduce the doseof pemafibrate, a salt thereof, or a solvate of any of these at the timeof the concomitant use.[51] A method of treating a patient in need of pemafibrate therapy,comprising a step of avoiding or suspending concomitant use ofpemafibrate, a salt thereof, or a solvate of any of these with an OATP1Binhibitor or reducing the dose of pemafibrate, a salt thereof, or asolvate of any of these, in order to suppress an increase in plasmaconcentration of pemafibrate in the concomitant use.[52] A method of treating a patient in need of pemafibrate therapy,comprising an optional step of avoiding or suspending concomitant use ofpemafibrate, a salt thereof, or a solvate of any of these with an OATP1Binhibitor or reducing the dose of pemafibrate, a salt thereof, or asolvate of any of these, in order to suppress an increase in plasmaconcentration of pemafibrate in the concomitant use.[53] Use of pemafibrate, a salt thereof, or a solvate of any of thesefor treating a patient in need of pemafibrate therapy, comprising a stepof avoiding or suspending concomitant use of pemafibrate, a saltthereof, or a solvate of any of these with an OATP1B inhibitor orreducing the dose of pemafibrate, a salt thereof, or a solvate of any ofthese, in order to suppress an increase in plasma concentration ofpemafibrate in the concomitant use.[54] Use of pemafibrate, a salt thereof, or a solvate of any of thesefor treating a patient in need of pemafibrate therapy, comprising anoptional step of avoiding or suspending concomitant use of pemafibrate,a salt thereof, or a solvate of any of these with an OATP1B inhibitor orreducing the dose of pemafibrate, a salt thereof, or a solvate of any ofthese, in order to suppress an increase in plasma concentration ofpemafibrate in the concomitant use.[55] A method of treating a patient in need of pemafibrate therapy,comprising a step of avoiding or suspending concomitant use ofpemafibrate, a salt thereof, or a solvate of any of these with a CYPinhibitor or reducing the dose of pemafibrate, a salt thereof, or asolvate of any of these, in order to suppress an increase in plasmaconcentration of pemafibrate in the concomitant use.[56] A method of treating a patient in need of pemafibrate therapy,comprising an optional step of avoiding or suspending concomitant use ofpemafibrate, a salt thereof, or a solvate of any of these with a CYPinhibitor or reducing the dose of pemafibrate, a salt thereof, or asolvate of any of these, in order to suppress an increase in plasmaconcentration of pemafibrate in the concomitant use.[57] Use of pemafibrate, a salt thereof, or a solvate of any of thesefor treating a patient in need of pemafibrate therapy, comprising a stepof avoiding or suspending concomitant use of pemafibrate, a saltthereof, or a solvate of any of these with a CYP inhibitor or reducingthe dose of pemafibrate, a salt thereof, or a solvate of any of these,in order to suppress an increase in plasma concentration of pemafibratein the concomitant use.[58] Use of pemafibrate, a salt thereof, or a solvate of any of thesefor treating a patient in need of pemafibrate therapy, comprising anoptional step of avoiding or suspending concomitant use of pemafibrate,a salt thereof, or a solvate of any of these with a CYP inhibitor orreducing the dose of pemafibrate, a salt thereof, or a solvate of any ofthese, in order to suppress an increase in plasma concentration ofpemafibrate in the concomitant use.

Effect of the Invention

According to the present invention, since an increase in plasmaconcentration of pemafibrate, a salt thereof, or a solvate of any ofthese is suppressed, a medicament for effective and safe use can beprovided.

DETAILED DESCRIPTION OF THE INVENTION

In the present specification, pemafibrate is a compound represented bythe following formula (3)

In the present invention, “pemafibrate, a salt thereof, or a solvate ofany of these” includes, in addition to pemafibrate itself, apharmaceutically acceptable salt of pemafibrate, and a solvate ofpemafibrate or a pharmaceutically acceptable salt of pemafibrate withwater and the like. In one embodiment of the present invention, thepemafibrate, a salt thereof, or a solvate of any of these ispemafibrate.

Pemafibrate, a salt thereof, or a solvate of any of these can beproduced according to the method described in, for example, WO2005/023777. The compounds may also be formulated according to themethods described in literatures in order to provide them as amedicament.

The medicament containing pemafibrate, a salt thereof, or a solvate ofany of these are preferably those for oral administration, and include atablet, a capsule, a granule and the like.

In the present invention, an “OATP1B inhibitor” is a drug that inhibitsthe action of organic anion-transporting polypeptides (OATP) 1B1 and/orOATP1B3 in the body, examples of which include clarithromycin,rifampicin, cyclosporine, a combination agent of lopinavir andritonavir, a combination agent of atazanavir and ritonavir, acombination agent of dalnavir and ritonavir, clopidogrel, eltrombopag, acombination agent of saquinavir and ritonavir, a combination agent oftipranavir and ritonavir, and gemfibrozil. It may also be an OATP1Binhibitor as described in the “Drug Interaction Guidelines for DrugDevelopment and Proper Information” (Final Draft), Evaluation andLicensing Division, Pharmaceutical and Food Safety Bureau, MHLW, Jul. 8,2014, the Guidelines (Guidance for Industry Drug InteractionStudies-Study Design, Data Analysis, Implications for Dosing, andLabeling Recommendations Draft Guidance (February 2012)) of the U.S.Food and Drug Administration, or the Guidelines (Guideline on theinvestigation of drug interactions (21 Jun. 2012)) of the EuropeanMedicines Agency. In one embodiment of the present invention, the OATP1Binhibitor is clarithromycin. In another embodiment of the presentinvention, the OATP1B inhibitor is rifampicin. In another embodiment ofthe present invention, the OATP1B inhibitor is cyclosporine. In anotherembodiment of the present invention, the OATP1B inhibitor isclopidogrel.

Also included in the OATP1B inhibitor are “a drug that inhibitsOATP1B1”, “a drug that inhibits OATP1B3”, and “a drug that inhibitsOATP1B1 and OATP1B3.” Examples of “a drug that inhibits OATP1B1” includecyclosporine, rifampicin, clarithromycin, a combination agent oflopinavir and ritonavir, combination of atazanavir and ritonavir, acombination agent of dalnavir and ritonavir, a combination agent ofsaquinavir and ritonavir, gemfibrozil, eltrombopag, a combination agentof tipranavir and ritonavir, and clopidogrel. Examples of “a drug thatinhibits OATP1B3” include cyclosporine, rifampicin, clarithromycin, acombination agent of lopinavir and ritonavir, a combination agent ofatazanavir and ritonavir, a combination agent of darnavir and ritonavir,a combination agent of saquinavir and ritonavir, and gemfibrozil.Examples of “a drug that inhibit OATP1B1 and OATP1B3” includecyclosporine, rifampicin, clarithromycin, a combination agent oflopinavir and ritonavir, a combination agent of atazanavir andritonavir, a combination agent of darnavir and ritonavir, a combinationagent of saquinavir and ritonavir, and gemfibrozil.

For a medicament containing an OATP1B inhibitor, those for oraladministration are preferable, and examples of which include a tablet, acapsule and a granule.

In the present invention, cytochrome P450 or “CYP” are enzymes involvedin metabolizing drugs in the liver, and “a CYP inhibitor” refers to adrug that inhibits the action of CYP in the body by ingestion. Examplesof “a CYP inhibitor” include, but are not limited to, “a CYP3Ainhibitor”, “a CYP2C8 inhibitor”, and “a CYP2C9 inhibitor.” Examples ofa drug that inhibits CYP3A include clarithromycin, cyclosporine,cobicystat, indinavir, itraconazole, ritonavir, telaprevir,voriconazole, nelfinavir, saquinavir, boceprevir, conibaptan,ketoconazole, a combination agent of lopinavir and ritonavir,mibefradil, nefazodone, posaconazole, telithromycin, fluconazole,amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, acombination agent of darunavir and ritonavir, diltiazem, erythromycin,fosamprenavir, imatinib, istradefillyne, miconazole, tofisopam,casopitant, dronedarone, and verapamil. Examples of “a drug thatinhibits CYP2C8” include gemfibrozil, clopidogrel, cyclosporine,deferasirox, and teriflunomide. Examples of “a drug that inhibitsCYP2C9” include fluorouracil derivatives, carmofur, sulfaphenazole,amiodarone, bucolome, cyclosporine, fluconazole, miconazole, andoxandrolone.

The “CYP inhibitor” may be a “drug that inhibits CYP3A”, “a drug thatinhibits CYP2C8”, or “a drug that inhibits CYP2C9” as described in the“Drug Interaction Guideline for Drug Development and Proper Information(Final Draft) (Evaluation and Licensing Division, Pharmaceutical andFood Safety Bureau, MHLW, Jul. 8, 2014), the guideline (Guidance forIndustry Drug Interaction Studies-Study Design, Data Analysis,Implications for Dosing, and Labeling Recommendations Draft Guidance(February 2012)) of the U.S. Food and Drug Administration, or theguideline (Guideline on the investigation of drug interactions (21 Jun.2012)) of the European Medicines Agency.

With respect to CYP enzymes, the U.S. Food and Drug Administrationgenerally defines a “potent inhibitor” as an inhibitor that, in clinicalevaluation, caused a >5-fold increase in plasma AUC values or a >80%decrease in clearance of CYP substrates (not limited to sensitive CYPsubstrates). The U.S. Food and Drug Administration generally defines a“moderate inhibitor” as an inhibitor that, in clinical evaluation,caused a >2-fold increase in AUC values, but a <5-fold increase inclearance of sensitive CYP substrates or a 50% to 80% decrease inclearance of sensitive CYP substrates when the inhibitor was given atthe highest approved dose and at the shortest dosing interval. Among theCYP3A inhibitors listed in the above U.S. Food and Drug Administrationguidelines, potent CYP3A inhibitors include boceprevir, clarithromycin,conivaptan, indinavir, itraconazole, ketoconazole, a combination agentof lopinavir and ritonavir, mibefradil, nefazodone, nelfinavir,posaconazole, ritonavir, saquinavir, telaprevir, voriconazole; moderateCYP3A inhibitors include amprenavir, aprepitant, atazanavir,ciprofloxacin, crizotinib, a combination agent of darnavir andritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatiniband verapamil. In the above U.S. Food and Drug Administrationguidelines, among the “drug that inhibits CYP2C8”, gemfibrozil is listedas a potent CYP2C8 inhibitor. In the above U.S. Food and DrugAdministration guidelines, among the “drug that inhibits CYP2C9,”amiodarone, fluconazole, miconazole, and oxandrolone are listed asmoderate CYP2C9 inhibitors.

In the present invention, “rifampicin” includes, not only rifampicinitself, but also a pharmaceutically acceptable salt thereof, and asolvate of rifampicin or its pharmaceutically acceptable salt with waterand the like. In one embodiment of the present invention, rifampicin isrifampicin as listed in the Japanese Pharmacopoeia, Seventeenth Edition.

In the present specification, “clarithromycin” includes not onlyclarithromycin itself, but also a pharmaceutically acceptable saltthereof, a solvate of clarithromycin or its pharmaceutically acceptablesalt with water and the like. In one embodiment of the presentinvention, clarithromycin is clarithromycin as listed in the JapanesePharmacopoeia, Seventeenth Edition.

In the present specification, “cyclosporine” includes not onlycyclosporine A represented by the following formula (4); but alsocyclosporine B, cyclosporine C, cyclosporine D, cyclosporine E,cyclosporine F, cyclosporine G, and cyclosporine H, which are analogs ofcyclosporine A; a pharmaceutically acceptable salt of cyclosporine; anda solvate of cyclosporine or its pharmaceutically acceptable salt withwater and the like.

In one embodiment of the present invention, cyclosporine is cyclosporineA, preferably cyclosporine listed in the Japanese Pharmacopeia,Seventeenth Edition (cyclosporine A).

In the present invention, “clopidogrel” includes, not only clopidogrelitself, but also a pharmaceutically acceptable salt thereof, and asolvate of clopidogrel or its pharmaceutically acceptable salt withwater and the like. Examples of salt of clopidogrel include, but are notlimited to, a hydrochloride, a sulfate, a bisulfate, a hydrobromide, anda taurocholate. In one embodiment of the present invention, clopidogrelis clopidogrel sulfate, preferably clopidogrel sulfate as listed in theJapanese Pharmacopoeia, Seventeenth Edition.

In the present invention, “a patient in need of pemafibrate therapy” or“a patient in need of treatment with pemafibrate, a salt thereof, or asolvate of any of these” includes, but not limited to, a patientexpressing one or more diseases selected from the group consisting of,for example, hyperlipidemia, dyslipidemia, arteriosclerosis, diabetesmellitus, diabetic complications, inflammation, non-alcoholicsteatohepatitis, primary biliary cirrhosis, and heart disease.

In the present invention, “treatment with an OATP1B inhibitor” refers toadministration of an OATP1B inhibitor for the treatment of a disease,and the OATP1B inhibitor used can differ depending on the disease to betreated. For example, rifampicin is used in the treatment of pulmonarytuberculosis and other tuberculosis, non-tuberculous mycobacteriosis,including Mycobacterium avium complex (MAC) disease, and leprosy.Clarithromycin is used for the treatment of general infectious diseases(superficial skin infections, deep skin infections, lymphangitis,lymphadenitis, chronic pyoderma, secondary infections caused by trauma,burns and surgical wounds, perianal abscess, pharyngeal/laryngitis,tonsillitis, acute bronchitis, pneumonia, lung abscess, secondaryinfection of chronic respiratory lesions, urethritis, cervicitis,infectious enteritis, otitis media, sinusitis, periodontitis,pericoronitis, or jaw inflammation by one or more bacteria selected fromthe group consisting of Staphylococcus, Streptococcus, Streptococcuspneumoniae, Moraxella (Branhamera) catarrhalis, Haemophilus influenzae,Legionella, Campylobacter, Peptostreptococcus, Chlamydia, andMycoplasma), nontuberculous mycobacterial disease includingMycobacterium avium complex (MAC) disease and Helicobacter pyloriinfection. Cyclosporine reduces rejection in organ transplantation(kidney, liver, heart, lung, pancreas, small intestine), rejection inbone marrow transplantation and graft-versus-host disease, Behcet'sdisease (if ocular symptoms are present) and other noninfectious uveitis(limited to active intermediate or posterior noninfectious uveitis thatmay be ineffective with existing therapy), psoriasis (psoriasis vulgaris(if skin rash is more than 30% of the whole body or refractory),pustular psoriasis, erythrodermic psoriasis, arthritic psoriasis),anemia (aplastic anemia (severe), pure red cell aplasia), nephroticsyndrome (frequent relapsing, or with resistance in steroid), myastheniagravis (in the treatment after thymectomy, when the effect of steroidsis insufficient or when it is difficult to administer steroids due toadverse reactions). It is also used for the treatment of atopicdermatitis (patients who are unable to achieve a satisfactory effectwith existing treatments). Clopidogrel is used to suppress recurrenceafter ischemic cerebrovascular disorder (excluding cardiogeniccerebrovascular embolism), to treat ischemic heart disease to whichpercutaneous coronary intervention (PCI) is applied (acute coronarysyndrome (unstable angina pectoris, non-ST-elevation myocardialinfarction, ST-elevation myocardial infarction), stable angina pectoris,old myocardial infarction), and to suppress thrombus and embolusformation in peripheral arterial disease. However, treatment with anOATP1B inhibitor is not limited to the treatment of these diseases.

In one embodiment of the present invention, the patient in need ofpemafibrate therapy is a patient in need of further treatment with anOATP1B inhibitor. Such patients include, a patient in need of additionalpemafibrate therapy during treatment with an OATP1B inhibitor, a patientin need of additional therapy with an OATP1B inhibitor duringpemafibrate therapy, and a patient in need of simultaneous start ofpemafibrate therapy and treatment with an OATP1B inhibitor.

In the present invention, “treatment with a CYP inhibitor” refers toadministration of a CYP inhibitor for the treatment of a disease, andthe CYP inhibitor to be used depends on the disease to be treated. Forexample, clarithromycin is used for the treatment of general infectiousdiseases (superficial skin infections, deep skin infections,lymphangitis, lymphadenitis, chronic pyoderma, secondary infectionscaused by trauma, burns and surgical wounds, perianal abscess,pharyngeal/laryngitis, tonsillitis, acute bronchitis, pneumonia lungabscess, secondary infection of chronic respiratory lesions, urethritis,cervicitis, infectious enteritis, otitis media, sinusitis,periodontitis, pericoronitis, or jaw inflammation by one or morebacteria selected from the group consisting of Staphylococcus,Streptococcus, Streptococcus pneumoniae, Moraxella (Branhamera)catarrhalis, Haemophilus influenzae, Legionella, Campylobacter,Peptostreptococcus, Chlamydia, and Mycoplasma), nontuberculousmycobacterial disease including Mycobacterium avium complex (MAC)disease and Helicobacter pylori infection. Cyclosporine reducesrejection in organ transplantation (kidney, liver, heart, lung,pancreas, small intestine), rejection in bone marrow transplantation andgraft-versus-host disease, Behcet's disease (if ocular symptoms arepresent) and other noninfectious uveitis (limited to active intermediateor posterior noninfectious uveitis that may be ineffective with existingtherapy), psoriasis (psoriasis vulgaris (if skin rash is more than 30%of the whole body or refractory), pustular psoriasis, erythrodermicpsoriasis, arthritic psoriasis), anemia (if erythroderma, arthriticpsoriasis), (aplastic anemia (severe), pure red cell aplasia), nephroticsyndrome (frequent relapsing, or with resistance in steroid), myastheniagravis (in the treatment after thymectomy, when the effect of steroidsis insufficient or when it is difficult to administer steroids due toadverse reactions). It is also used for the treatment of atopicdermatitis (patients who are unable to achieve a satisfactory effectwith existing treatments). Clopidogrel is used to suppress recurrenceafter ischemic cerebrovascular disorder (excluding cardiogeniccerebrovascular embolism), to treat ischemic heart disease to whichpercutaneous coronary angioplasty (PCI) is applied (acute coronarysyndrome (unstable angina pectoris, non-ST-elevation myocardialinfarction, ST-elevation myocardial infarction), stable angina pectoris,old myocardial infarction), and to suppress thrombus and embolusformation in peripheral arterial diseases. However, treatment with a CYPinhibitor is not limited to the treatment of these diseases.

In one embodiment of the present invention, the patient in need ofpemafibrate therapy is a patient in need of further treatment with a CYPinhibitor. Such patients include, for example, a patient in need offurther pemafibrate therapy during treatment with a CYP inhibitor, apatient in need of additional treatment with a CYP inhibitor duringpemafibrate therapy, and a patient in need of simultaneous start ofpemafibrate therapy and treatment with a CYP inhibitor.

In the present invent ion, a “concomitant use” ref ere to a patient'staking two or more medicaments or to let a patient take two or moremedicaments. In one embodiment of the present invention, when thepatient takes two medicaments, for example, the patient may take twomedications simultaneously or one by one at an interval.

Investigations by the present inventors revealed that the plasmaconcentration of pemafibrate were increased when pemafibrate, a saltthereof, or a solvate of any of these was used concomitant withrifampicin, as compared with administration of pemafibrate, a saltthereof, or a solvate of any of these alone (see Examples below). Suchan increase in plasma concentration of pemafibrate may cause unexpectedside effects. Therefore, in the present invention, in order to suppresssuch an increase in plasma concentration of pemafibrate, the concomitantuse is avoided or suspended, or the dose of pemafibrate, a salt thereof,or a solvate of any of these is reduced.

Rifampicin is a drug known to act as an inhibitor of OATP1B1 and OATP1B3by a single administration, and it is conceivable that its inhibitoryeffect is involved in increasing plasma concentration of pemafibrate.That is, concomitant use of an OATP1B inhibitor with pemafibrate, a saltthereof, or a solvate of any of these may increase plasma concentrationof pemafibrate. Therefore, in order to suppress the increase in theplasma concentration of pemafibrate, the concomitant use was avoided orsuspended, or the dose of pemafibrate, a salt thereof, or a solvate ofany of these was reduced.

Clarithromycin is known to inhibit CYP3A, OATP1B1, and OATP1B3, therebycausing drug interactions, and may be involved in increasing plasmaconcentration of pemafibrate. That is, if the drug inhibits CYP3A,OATP1B1, and OATP1B3, the plasma concentration of pemafibrate may beincreased by concomitant use of pemafibrate, a salt thereof, or asolvate of any of these. Therefore, in order to suppress the increase inthe plasma concentration of pemafibrate, the concomitant use was avoidedor suspended, or the dose of pemafibrate, a salt thereof, or a solvateof any of these was reduced.

In the present invention, examples of “a drug that inhibits CYP3A,OATP1B1, and OATP1B3” include clarithromycin, cyclosporine, andHIV-protease inhibitors. Examples of HIV protease inhibitors includeatazanavir, a salt thereof, or a solvate of any of these (atazanavirsulfate etc.), indinavir, a salt thereof, or a solvate of any of these(indinavir sulfate ethanol adduct etc.), saquinavir, a salt thereof, ora solvate of any of these (saquinavir mesylate etc.), darnavir, a saltthereof, or a solvate of any of these (darnavir ethanol adduct etc.),nelfinavir, a salt thereof, or a solvate of any of these (nelfinavirmesylate etc.), phosamprenavir, a salt thereof, or a solvate of any ofthese (phosamprenavir calcium hydrate etc.), ritonavir, a salt thereof,or a solvate of any of these or a solvate, and lopinavir, a saltthereof, or a solvate of any of these, and in particular ritonavir, asalt thereof, or a solvate of any of these, are known to inhibit CYP3A,OATP1B1 and OATP1B3.

In one embodiment of the present invention, “a medicament comprising adrug that inhibits CYP3A, OATP1B1, and OATP1B3” includes a concomitantdrug that exhibits other pharmacological action than a medicament thatincludes either clarithromycin, cyclosporine, or an HIV-proteaseinhibitor as the sole pharmacological action compound. The abovecombination agents include a combination agent of ritonavir andlopinavir (e.g., Kaletra), a combination agent of ritonavir andombitavir hydrate and palitaprevir hydrate (VIEKIRAX), a combinationagent of ritonavir and darnavir ethanol adduct, and a combination agentof darnavir ethanol adduct and cobicistat (Prezcobix).

Concomitant use of “a drug that inhibits CYP3A” and “a drug thatinhibits OATP1B1 and OATP1B3” may inhibit CYP3A, OATP1B1, and OATP1B3,and may increase plasma concentration of pemafibrate by administeringpemafibrate, a salt thereof, or a solvate of any of these to the samepatients. Therefore, caution should be exercised when pemafibrate, asalt thereof, or a solvate of any of these is used concomitant with “adrug that inhibits CYP3A” or “a drug that inhibits OATP1B1 and OATP1B3,”and avoiding or suspending the concomitant use, or reducing the dose ofpemafibrate, a salt thereof, or a solvate of any of these can suppressthe increase in plasma concentration of pemafibrate.

Cyclosporine is also known to inhibit CYP3A, CYP2C8, CYP2C9, OATP1B1,and OATP1B3, and to cause drug interactions, and it is considered thatcyclosporine is involved in increasing plasma concentration ofpemafibrate. That is, if a drug inhibits CYP3A, CYP2C8, CYP2C9, OATP1B1,and OATP1B3, plasma concentration of pemafibrate may be increased byconcomitant use of pemafibrate, a salt thereof, or a solvate of any ofthese with such a drug. Therefore, in order to suppress the increase inthe plasma concentration of pemafibrate, the present inventorsdetermined to avoid or suspend the concomitant use, or reduce the doseof pemafibrate, a salt thereof, or a solvate of any of these.

In addition, concomitant use of “a drug that inhibits CYP3A”, “a drugthat inhibits CYP2C8”, “a drug that inhibits CYP2C9”, and “a drug thatinhibits OATP1B1 and OATP1B3” may inhibit CYP3A, CYP2C8, CYP2C9, OATP1B1and OATP1B3, and may increase the plasma concentration of pemafibrate byadministering pemafibrate, a salt thereof, or a solvate of any of theseto the same subject. Therefore, care must be taken when pemafibrate, asalt thereof, or a solvate of any of these is concomitantly used withone or more drugs selected from the group consisting of “a drug thatinhibits CYP3A”, “a drug that inhibits CYP2C8”, “a drug that inhibitsCYP2C9” and “a drug that inhibits OATP1B1 and OATP1B3”. Increase in theplasma concentration of pemafibrate can be suppressed by avoiding orsuspending the concomitant use or by reducing the dose of pemafibrate, asalt thereof, or a solvate of any of these.

Clopidogrel is also known to inhibit CYP2C8 and OATP1B1 and cause druginteract ions, and may be involved in increasing plasma concentration ofpemafibrate. That is, if the drug inhibits CYP2C8 and OATP1B1, theplasma concentration of pemafibrate may be increased by concomitant usewith pemafibrate, a salt thereof, or a solvate of any of these orsolvates thereof. Therefore, in order to suppress an increase in theplasma concentration of pemafibrate, the present inventors determined toavoid or suspend the concomitant use, or to reduce the dose ofpemafibrate, a salt thereof, or a solvate of any of these.

In addition, concomitant use of “a drug that inhibits CYP2C8” with “adrug that inhibits OATP1B1” may inhibit CYP2C8 and OATP1B1, and ifpemafibrate, a salt thereof, or a solvate of any of these is furtheradministered to the same patients, the plasma concentration ofpemafibrate may be increased. Therefore, caution should be exercisedwhen using pemafibrate, a salt thereof, or a solvate of any of theseconcomitant with “a drug that inhibits CYP2C8” or “a drug that inhibitsOATP1B1”, and avoidance or suspension of such concomitant use orreduction of pemafibrate, a salt thereof, or a solvate of any of thesecan suppress an increase in plasma concentration of pemafibrate.

In the present specification, the “step of avoiding or suspending theconcomitant use with the pharmaceutical containing the OATP1B inhibitor”is not particularly limited, and includes, for example, any one of thefollowing steps (i) to (vii).

(i) Recommending a patient to contraindicate the use of pemafibrate, asalt thereof, or a solvate of any of these concomitant with a drugcontaining an OATP1B inhibitor because of increased plasma concentrationof pemafibrate.

(ii) Recommending a patient to avoid or discontinue concomitant use ofpemafibrate, a salt thereof, or a solvate of any of these with amedicament containing an OATP1B inhibitor because of increased plasmaconcentration of pemafibrate.

(iii) Recommending the subject that the use of a medicament containingan OATP1B inhibitor should be suspended prior to the use of a medicamentcontaining pemafibrate, a salt thereof, or a solvate of any of these.

(iv) Recommending a patient to contraindicate concomitant use ofpemafibrate, a salt thereof, or a solvate of any of these with amedicament containing an OATP1B inhibitor because of increased plasmaconcentration of pemafibrate.

(v) Recommending a patient to avoid or discontinue concomitant use ofpemafibrate, a salt thereof, or a solvate of any of these with amedicament containing an OATP1B inhibitor because of increased plasmaconcentration of pemafibrate in principle.

(vi) Recommending a patient to administer a medication containingpemafibrate, a salt thereof, or a solvate of any of these with cautionagainst the onset of adverse reactions, because the plasma concentrationof pemafibrate are increased by concomitantly administering it with amedication containing an OATP1B inhibitor. Recommending patients toadminister a medication containing pemafibrate, a salt thereof, or asolvate of any of these with caution against the onset of adversereactions.

(vii) Any one of the steps selected from the group consisting of (i) to(vi) which is carried out after explaining to the patient that thenormal metabolism of pemafibrate, a salt thereof, or a solvate of any ofthese is inhibited by taking a medicament comprising an OATP1Binhibitor.

The above (i) to (vii) can replace the “OATP1B inhibitor” with any drug,and can be read as a step for an arbitrary drug. The arbitrary drug isone or more drugs selected from the group consisting of, for example,but not limited to, a CYP inhibitor, a drug that inhibits CYP3A, a drugthat inhibits CYP2C8, a drug that inhibits CYP2C9, a drug that inhibitsOATP1B1 and OATP1B3, and a drug that inhibits OATP1B1.

In the present invention, “dose” means an amount of active ingredientused per day and is expressed in units of g/day or mg/day. In oneembodiment of the present invention, the dose of pemafibrate, a saltthereof, or a solvate of any of these to a patient in need ofpemafibrate therapy is preferably 0.1 to 0.4 mg/day. If the patientfurther requires treatment with an OATP1B inhibitor, less than 0.4mg/day is preferable, and 0.1 to 0.2 mg/day is more preferable. In oneembodiment of the present invention, when pemafibrate is usedconcomitantly with clarithromycin or clopidogrel, it is preferable thatthe daily dose of pemafibrate be 0.1 mg and the maximal dose be up to0.2 mg per day, but the dose is not limited thereto. It is alsopreferable that pemafibrate, a salt thereof, or a solvate of any ofthese be administered in a manner that the above daily dose is dividedinto twice.

In the present invention, “a step of reducing the dose of pemafibrate, asalt thereof, or a solvate of any of these” means changing the dose ofpemafibrate, a salt thereof, or a solvate of any of these selected fromthe group consisting of from 0.4 mg/day to 0.35 mg/day, from 0.4 mg/dayto 0.3 mg/day, from 0.4 mg/day to 0.25 mg/day, from 0.4 mg/day to 0.2mg/day, from 0.4 mg/day to 0.15 mg/day, from 0.4 mg/day to 0.1 mg/day,from 0.4 mg/day to 0.05 mg/day, from 0.35 mg/day to 0.3 mg/day, from0.35 mg/day to 0.25 mg/day, and from 0.35 mg/day to 0.2 mg/day, and from0.35 mg/day to 0.15 mg/day, from 0.35 mg/day to 0.1 mg/day, from 0.35mg/day to 0.05 mg/day, from 0.3 mg/day to 0.25 mg/day, from 0.3 mg/dayto 0.2 mg/day, from 0.3 mg/day to 0.15 mg/day, from 0.3 mg/day to 0.05mg/day, from 0.25 mg/day to 0.2 mg/day, from 0.25 mg/day to 0.15 mg/day,0.25 mg/day to 0.1 mg/day, from 0.25 mg/day to 0.05 mg/day, from 0.2mg/day to 0.15 mg/day, from 0.2 mg/day to 0.1 mg/day, from 0.2 mg/day to0.05 mg/day, from 0.15 mg/day to 0.1 mg/day, from 0.15 mg/day to 0.05mg/day, and from 0.1 mg/day to 0.05 mg/day. Among these, it ispreferable to reduce the dose of pemafibrate, a salt thereof, or asolvate of any of these, compared with the dose when pemafibrate isadministered alone, to ½ or less.

In the present invention, “reducing the dose of pemafibrate, a saltthereof, or a solvate of any of these” can be expressed, for example, as“reducing the amount of pemafibrate, a salt thereof, or a solvate of anyof these to be administered”, “reducing the amount of pemafibrate, asalt thereof, or a solvate of any of these” or “lowering the dose ofpemafibrate, a salt thereof, or a solvate of any of these.”

In another embodiment of the present invention, the “step of avoiding orsuspending concomitant use” and the “step of reducing the dose ofpemafibrate, a salt thereof, or a solvate of any of these” forsuppressing an increase in plasma concentration of pemafibrate can beperformed as required, and embodiments thereof include, for example, themedicaments recited in [47] and [49], the pharmaceutical kits recited in[48] and [50], the methods for treatment recited in [52] and [56], andthe use for treatment recited in [54] and [58], and the like.

In one embodiment of the present invention, the dose of clarithromycinto a patient in need of treatment with clarithromycin is preferably from200 to 1,600 mg/day, preferably 200 to 800 mg/day for the treatment ofgeneral infectious diseases, 400 to 1,600 mg/day for the treatment ofnon-tuberculous mycobacteriosis, and 200 to 800 mg/day for the treatmentof Helicobacter pylori infections.

In one embodiment of the present invention, the dose of clopidogrel, asalt thereof, or a solvate of any of these to a patient in need oftreatment with clopidogrel, a salt thereof, or a solvate of any of theseis 75 to 400 mg/day, preferably 75 to 300 mg/day as clopidogrel, morepreferably 391.5 mg/day of clopidogrel sulfate (equivalent to 300 mg/dayof clopidogrel) on day 1 and 97.875 mg/day of clopidogrel sulfate(equivalent to 75 mg/day of clopidogrel) on and after day 2 ofadministration.

One embodiment of the present invention includes a pharmaceutical kitcomprising (A) a medicament comprising pemafibrate, a salt thereof, or asolvate of any of these or solvate thereof as an active ingredient; and(B) an instruction to avoid or suspend concomitant use of the (A) and amedicament comprising an OATP1B inhibitor or to reduce the dose ofpemafibrate, a salt thereof, or a solvate of any of these.

In this specification, “an instruction to avoid or suspend concomitantuse” is an instruction describing a situation in which concomitant useof two specific medicaments should be avoided or suspended. In oneembodiment of the present invention, the “instruction to avoid orsuspend concomitant use of Medicament A and Medicament B” is notparticularly limited, but includes, for example, an instruction forinstructing (a) to (h) below.

(a) Do not administer Medicament B to a patient receiving Medicament A.

(b) Do not concomitantly use Medicament A and Medicament B

(c) In principle, Medicament A should not be administered to a patientreceiving Medicament B, but should be administered with care whenparticularly necessary.

(d) In principle, Medicament A and Medicament B should not be usedconcomitantly, but concomitant use should be made with caution only whenit is judged that the concomitant use is unavoidable for treatment.

(e) Caution should be exercised when administering Medicament A to apatient receiving Medicament B.

(f) Caution should be exercised when Medicament A and Medicament B areused concomitantly.

(g) If the patient is taking Medicament B, suspend taking medicament Bbefore using Medicament A.

(h) If the patient is taking Medicament B, explain the currentcompliance status to the physician or pharmacist before using MedicamentA.

In the present invention, “instruction” include a package insert, apackage label, or a user manual, and include, but are not limited to, apackage insert, an interview form, a prescribing information, a patientinformation leaflet, for example.

The following examples and test example are given to explain the presentinvention in more detail, but the present invention is not limitedthereto.

EXAMPLES Example 1: Drug Interaction Study of Pemafibrate withRifampicin

A study was conducted to investigate the effect of rifampicin on thepharmacokinetics of pemafibrate in healthy adult subjects.

[Subject]

20 healthy adults

[Dose and Administration]

Subjects were orally administered on the following schedule. Theadministration of 0.4 mg of pemafibrate on Days 1 and 4 was carried outunder fasting for at least 8 hours, and the fasting was maintained for 4hours after the administration.

-   -   Day 1: Pemafibrate 0.4 mg alone    -   Day 4: A single dose of 0.4 mg of pemafibrate plus 600 mg of        rifampicin    -   Days 5-6: Rifampicin 600 mg alone        [Measurement]

Plasma concentration of pemafibrate was measured on blood samples frompatients taken prior to and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12,14, 16, 24, 36, 48, 72 hours after administration of the drug on Days 1and 4.

For estimates of the C_(max) of pemafibrate and the area under theconcentration-time curves (AUC_(0-inf)) up to infinity hours, thegeometric mean values and the ratios of the geometric mean values forconcomitant administration to those for the single administration areshown in Table 1. As can be seen from Table 1, concomitantadministration of pemafibrate and rifampicin resulted in an increase inthe plasma concentration of pemafibrate compared with administration ofpemafibrate alone.

TABLE 1 Ratio (concomitant use/ Single Concomitant single use) 90%Parameter adminitration administration confidence interval Cmax 5.67253.512 9.436 (ng/mL) 8.3626-10.6419 AUC_(0-inf) 20.069 218.774 10.9009(ng•h/mL) 9.9154-11.9844

Example 2: Drug Interaction Study of Pemafibrate with Clarithromycin

A study was conducted to investigate the effect of clarithromycin on thepharmacokinetics of pemafibrate in healthy adult subjects.

[Subject]

20 healthy adult subjects

[Dose and Administration]

Subjects were orally administered on the following schedule. Theadministration of 0.4 mg of pemafibrate on Days 1 and 9 was carried outunder fasting for at least 8 hours, and the fasting was maintained for 4hours after the administration.

-   -   Day 1: Pemafibrate 0.4 mg alone    -   Day 4 to 8: Clarithromycin 500 mg twice per day (1000 mg/day)    -   Day 9: Pemafibrate 0.4 mg single dose and Clarithromycin 500 mg        twice per day (1000 mg/day)    -   Day 10 to 11: Clarithromycin 500 mg twice per day (1000 mg/day)        Measurement

Plasma concentration of pemafibrate was measured on blood samples frompatients collected prior to and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10,12, 14, 16, 24, 36, 48, 72 hours after administration of 0.4 mg ofpemafibrate on Days 1 and 9.

For estimates of the C_(max) of pemafibrate and the area under theconcentration-time curves (AUC_(0-inf)) up to infinity hours, thegeometric mean values and the ratios of the geometric mean values forconcomitant administration to those for the single administration areshown in Table 2. As can be seen from Table 2, concomitantadministration of pemafibrate and clarithromycin resulted in an increasein the plasma concentration of pemafibrate compared with administrationof pemafibrate alone.

TABLE 2 Ratio (concomitant use/ Single Concomitant single use) 90%Parameter administration administration confidence interval Cmax 4.67311.331 2.4246 (ng/mL) 2.1632-2.7174 AUC_(0-inf) 17.006 35.670 2.0975(ng•h/mL) 1.9158-2.2964

Example 3: Drug Interaction Study of Pemafibrate with Cyclosporine

A study was conducted to investigate the effect of cyclosporine on thepharmacokinetics of pemafibrate in healthy adult subjects.

[Subject]

20 healthy adults

[Dose and Administration]

Subjects were orally administered on the following schedule. Drugadministration was carried out under fasting for at least 8 hours, andfasting was maintained for 4 hours after administration.

-   -   Day 1: Pemafibrate 0.4 mg alone    -   Day 4: Combined single dose of 0.4 mg of pemafibrate and 600 mg        of cyclosporine (Neoral® or its equivalent)        [Measurement]

Plasma concentration of pemafibrate was measured on blood samples frompatients taken prior to and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12,14, 16, 24, 36, 48, 72 hours after administration of the drug on Days 1and 4.

For estimates of the C_(max) of pemafibrate and the area under theconcentration-time curves (AUC_(0-inf)) up to infinity hours, thegeometric mean values and the ratios of the geometric mean values forconcomitant administration to those for the single administration areshown in Table 3. As can be seen from Table 3, concomitantadministration of pemafibrate and cyclosporine resulted in an increasein the plasma concentration of pemafibrate compared with administrationof pemafibrate alone.

TABLE 3 Ratio (concomitant use/ Single Concomitant single use) 90%Parameter administration administration confidence interval Cmax 4.59341.175 8.9644 (ng/mL) 7.5151-10.6931 AUC_(0-inf) 13.388 187.363 13.9947(ng•h/mL) 12.6175-15.5223

Example 4: Drug Interaction Study of Pemafibrate with Clopidogrel

A study was conducted to investigate the effect of clopidogrel on thepharmacokinetics of pemafibrate in healthy adult subjects.

[Subject]

20 healthy adults

[Dose and Administration]

Subjects were orally administered on the following schedule. Pemafibrateadministration on Days 1, 4, and 7 was carried out under fasting for atleast 8 hours and maintained fasting for 4 hours after administration.

-   -   Day 1: Pemafibrate 0.4 mg alone    -   Day 4: A single dose of 0.4 mg of pemafibrate plus 391.5 mg of        clopidogrel sulfate (equivalent to 300 mg of clopidogrel)    -   Day 5 to 6: Clopidogrel Sulfate 91.875 mg (equivalent to        Clopidogrel 75 mg) alone    -   Day 7: A single dose of 0.4 mg of pemafibrate and 91.875 mg of        clopidogrel sulfate (equivalent to 75 mg of clopidogrel)    -   Day 8 to 9: Clopidogrel Sulfate 91.875 mg (equivalent to        Clopidogrel 75 mg) alone        Measurement

Plasma concentration of pemafibrate was measured on blood samples frompatients taken prior to and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12,14, 16, 24, 36, 48, 72 hours after administration of the drug on Days 1,4, and 7.

For estimates of the C_(max) of pemafibrate and the area under theconcentration-time curves (AUC_(0-inf)) up to infinity hours, thegeometric mean values and the ratios of the geometric mean values of thesingle-dose concomitant administration (Day 4) to those for the singleadministration (Day 1) are shown in Table 4. As can be seen from Table4, concomitant administration of pemafibrate and clopidogrel resulted inan increase in the plasma concentration of pemafibrate compared withadministration of pemafibrate alone.

TABLE 4 Ratio (concomitant use/ Single Concomitant single use) 90%Parameter administration administration confidence interval Cmax 4.76617.0799 1.4855 (ng/mL) 1.3915-1.5858 AUC_(0-inf) 16.0763 38.1452 2.3728(ng•h/mL) 2.2473-2.5052

For the C_(max) and AUC_(0-inf) of pemafibrate, the geometric meanvalues and the ratios of the geometric mean values for concomitantadministration after repeated administration of clopidogrel (day 7) tothose for the single administration (day 1) are shown in Table 5. As canbe seen from Table 5, concomitant administration of pemafibrate andclopidogrel resulted in an increase in the plasma concentration ofpemafibrate compared with administration of pemafibrate alone.

TABLE 5 Ratio (concomitant use/ Single Concomitant single use) 90%Parameter administration administration confidence interval Cmax 4.76616.3935 1.3415 (ng/mL) 1.2583-1.4302 AUC_(0-inf) 16.0763 33.5611 2.0876(ng•h/mL) 1.9811-2.98

INDUSTRIAL APPLICABILITY

The present invention can avoid an increase in plasma concentration ofpemafibrate, a salt thereof, or a solvate of any of these. Thus, amedicament can be provided for the effective and safe use ofpemafibrate, a salt thereof, or a solvate of any of these.

The invention claimed is:
 1. A method of treating dyslipidemia in apatient who is taking an original daily dose of 0.4 mg per day ofpemafibrate or a pharmaceutically acceptable salt thereof, comprisingthe steps of: i) reducing the original daily dose to an adjusted dailydose range of 0.1 mg to 0.2 mg pemafibrate or a pharmaceuticallyacceptable salt thereof, and ii) administering clopidogrel and theadjusted once-daily dose.
 2. The method of claim 1, comprising reducingthe original daily dose to an adjusted daily dose of 0.2 mg pemafibrateor a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,comprising administering 75 mg/day clopidogrel.
 4. The method of claim1, further comprising, after step (ii), eliminating any administrationof clopidogrel to the patient, and resuming the original daily dose. 5.A method of treating dyslipidemia in a patient who is taking an originaldaily dose of 0.4 mg per day of pemafibrate or a pharmaceuticallyacceptable salt thereof, comprising the steps of: i) reducing theoriginal daily dose to an adjusted daily dose of 0.2 mg pemafibrate or apharmaceutically acceptable salt thereof, and ii) administeringclopidogrel and the adjusted once-daily dose.